Metal fume fever is a common occupational illness caused by inhalation of freshly generated zinc oxide and other metal fumes. This illness is characterized by fever, systemic symptoms, and mild lung inflammation with onset several hours after the acute exposure. Repeated exposure results in adaptation with reduction in symptoms and febrile response. There is little information regarding dose-response relationships in naive and chronically exposed individuals, the nature of adaptation to the acute response, or the mechanism by which zinc oxide exposure causes metal fume fever. Our laboratory has developed a quantitative zinc oxide fume generating, monitoring, and exposure system for animal and human subjects. Using this system, we have previously demonstrated: 1) systemic effects in humans at the current OSHA PEL of 5 mg/m3; 2) induction of human zinc-binding protein (metallothionein) after exposure; 3) acute lung inflammation in animals exposed below the PEL; and 4) alterations in cytokine release from guinea pig lung inflammatory cells. To further understand acute and adaptive responses to zinc oxide exposure, and to determine the mechanism by which it causes metal fume fever, the following hypotheses will be tested: 1) acute, febrile, and pulmonary responses to exposure in human subjects occur at, and below, the current OSHA PEL; 2) adaptive responses to chronic exposures in humans do not eliminate lung inflammatory changes; 3) adaptation involves changes in systemic metallothionein gene induction; 4) mechanism of metal fume fever and adaptation involves release of cytokines and a modulation of their response at a central or peripheral level in zinc oxide-exposed animals. These studies will be accomplished using an integrated multi-disciplinary approach, and should yield important insights into the genesis and adaptation of this debilitating occupational illness.